There is an increasing need to find new molecules that can effectively modulate a wide range of biological processes. Rational drug design methodologies which have been used historical to design new drugs and other useful compositions, have been limited by the fact that the new drugs are generally derived from a known starting point. Recently, new technologies have focused on non-rational drug design. These methodologies generally rely upon the use of combinatorial libraries of randomly created polymers. Some work has been done to optimize the "randomness" of peptide libraries. Rutter and Santi, U.S. Pat. No. 5,010,175, focuses upon identifying the binding rate constants of amino acid units and modifying incorporation of each amino acid depending upon the rate constant for a given amino acid. Lam, et al., PCT/US91/04666 filed Jul. 1, 1991, teach coupling amino acid units to a solid support, mixing the solid supports, and aliquoting the solid supports into equal portions. Thereafter the coupling, aliquoting, and mixing are repeated. Similarly, Owens, et al., 1991, Biochem. Biophys. Res. Comm., 181, 402-408, teach several coupling reactions each with different amino acids conducted simultaneously and then combined to generate a near equimolar mixture before coupling additional residues. Houghten et al., PCT/US91/08694 filed Nov. 20, 1991, teach a process for the synthesis of a complex mixture pool of solid support-coupled monomeric repeating units, such as amino acids, by reacting the monomeric units with solid supports and mixing the solid supports linked to the monomeric units to form a reaction product pool. Thereafter the reaction pool is separated into a number of aliquots of equal weight and the process is repeated to produce peptides of a desired length.
As compared to amino acids, nucleotide monomers and chemical species related thereto represent a very different class of chemicals having very different properties. These difference are of such extent so as to require very dissimilar chemistries to prepare polymeric species from the monomers. Additionally they present other problems and differences such as purification that must be overcome in the preparation of random libraries. Until now, little work has been done to optimize the preparation and use of nucleotide based combinatorial libraries. Huse, et al., PCT/US91/05939 filed Aug. 20, 1991, teach a method of synthesizing oligonucleotides having random tuplets (i.e. doublets, triplets, or quartets) using individual monomers whereby monomers are sequentially coupled in separate reaction vessels on separate supports. Thereafter the supports are mixed, and the mixture is aliquoted. The tuplets are designed so as to provide the entire genetic code, excepting those degenerate codons.
Methods of reducing bias by equalizing binding of each unit in an oligonucleotide pool are greatly desired. These and other objects are provided by the present invention.